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Cited by 1,247Lung Cancer Treatments and MutationsMelanoma and MAPK PathwaysProtein Kinase Regulation and GTPase Signaling

Acquired Resistance to KRAS G12C Inhibition in Cancer

Open access
Awad, Mark M., Liu, Shengwu, Rybkin, Igor I., Arbour, Kathryn C., Dilly, Julien, Zhu, Viola W., Johnson, Melissa L., Heist, Rebecca S. +29 more·2021·New England Journal of Medicine
DOI 10.1056/nejmoa2105281PMC PMC8864540
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Abstract

BACKGROUND: ). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: inhibitors. RESULTS: inhibitors. CONCLUSIONS: inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).

Integrity signals

Registry

Crossref · 10.1056/nejmoa2105281

Cites

26 of 26 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

21 of 33 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The mechanisms of acquired resistance to adagrasib and sotorasib are currently unknown.

    “The mechanisms of acquired resistance to these therapies are currently unknown.”
    • Also stated in: § CONCLUSIONS · plain
      “Little is currently known about the clinical mechanisms of resistance to KRASG12C inhibition.6,7,15-17”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [6] source
    • cites [7] source

      The Results section on the CRISPR/Cas9 screen says KEAP1 loss may represent a mechanism of intrinsic or acquired resistance to MRTX849, but does not establish whether acquired-resistance mechanisms are currently unknown. The Discussion addresses transient or submaximal MRTX849 responses, not acquired resistance to both adagrasib and sotorasib. Searches for acquired resistance and sotorasib found no passage settling the claim. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [15] source

      The Introduction and Discussion address rapid adaptive feedback resistance to KRASG12C inhibition, not whether mechanisms of acquired resistance to adagrasib and sotorasib are unknown. Searches for acquired resistance and long-term treatment found no passage addressing that specific claim; the indexed copy provides no page numbers. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [16] source

      The opening Abstract says how cancer cells bypass KRASG12C inhibition was not understood. But the paper then identifies a mechanism of rapid adaptive escape; it does not establish that the mechanisms of acquired resistance to adagrasib and sotorasib remained unknown. Rapid escape shortly after treatment is not the same claim as acquired resistance to those therapies. (LLM, conf=0.80)

      Experimental — accuracy not yet measured
    • cites [17] source

      The Introduction identifies EGFR reactivation as a mechanism of adaptive resistance to KRAS G12C inhibition in colorectal cancer. The Discussion says combination treatment could limit the emergence of acquired resistance, but does not state whether the mechanisms of acquired resistance to AMG510 (sotorasib) or MRTX849 (adagrasib) were known or unknown. No page numbers are available in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Premisecitation

    Despite clinical benefit, acquired resistance to single-agent KRASG12C inhibitor therapy eventually occurred in most patients.

    “Despite the clinical benefit that was observed for many patients treated with KRASG12C inhibitors, acquired resistance to single-agent therapy eventually occurred in most patients.”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [6] source
    • cites [7] source

      The Results section, “MRTX849 Antitumor Activity Translates to RECIST Responses in Cancer Patients” (page unavailable), reports clinical responses in two patients, both of whom remained on treatment at the reported follow-up. The Discussion describes a lack of durable regression in 9 of 26 tumor models, but does not establish that acquired resistance eventually occurred in most patients receiving single-agent therapy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [15] source

      The Discussion (page unavailable) describes promising initial clinical activity with single-agent KRASG12C inhibition and says the durability of benefit may be limited. It does not report that most patients who benefited eventually developed acquired resistance; the clinical figure it gives is an initial response rate, not a rate of acquired resistance. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [16] source

      The Abstract reports early partial responses in about 50% of lung cancer patients and describes rapid escape from inhibition in subsets of cancer cells. It does not report that acquired resistance eventually occurred in most patients receiving single-agent therapy; that clinical frequency and timeline are unsupported. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [17] source

      The Abstract reports clinical benefit for most patients with KRAS G12C-mutant NSCLC and limited response in colorectal cancer. The Introduction describes adaptive resistance in cell lines and patient-derived models, but our copy does not report that acquired resistance eventually occurred in most patients receiving single-agent therapy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Interpretationreasoning

    These resistance mutations probably increase the fraction of KRAS protein in the active GTP-bound form that does not bind the drug.

    “These resistance mutations probably increase the fraction of KRAS protein in the active GTP-bound form that does not bind to the drug.4”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Premisecitation

    A recent case described an acquired Y96D switch II pocket mutation at low variant allele frequency in ctDNA at the time of acquired resistance to adagrasib.

    “In recent work, a case was described of an acquired Y96D switch II pocket mutation identified at a low variant allele frequency in ctDNA at the time of acquired resistance to adagrasib.23”
    Quote in the paperNot a substantial claim1 of 1 sources checked
  • Findingown data

    In several patients, multiple resistance mechanisms were identified simultaneously through ctDNA analysis.

    “In several patients, multiple mechanisms of resistance were identified simultaneously through ctDNA analysis”
    Quote in the paperNot a substantial claim
  • May combine two claims. 28
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Premisecitation

    Compounds bind covalently to cysteine 12 in the switch II pocket of GDP-bound KRASG12C, preventing oncogenic signaling and causing tumor regressions in preclinical models.

    “compounds have been identified that bind covalently to cysteine 12 within the switch II pocket of the GDP-bound form of the KRASG12C protein, preventing oncogenic signaling and causing potent tumor regressions in preclinical models.3-7”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [3] source

      The paper’s structural and cellular-results passages support covalent binding at cysteine 12 in the switch-II pocket of GDP-bound KRAS(G12C) and impaired signaling-related interactions. They do not support potent tumor regressions in preclinical models: the reported effects are in lung cancer cell lines, and the discussion says the compounds require further optimization before in vivo assessment. The relevant passages have no page numbers in our copy. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
    • cites [4] source

      The paper’s main text (indexed under Abstract; page unavailable) reports that ARS853 preferentially binds GDP-bound KRASG12C and suppresses KRAS-GTP and downstream signaling in mutant lung cancer cells. The passages do not establish covalent binding specifically to cysteine 12 in the switch II pocket, and they report cell-line growth inhibition and apoptosis—not potent tumor regressions in preclinical models. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [5] source
      Experimental — accuracy not yet measured
    • cites [6] source
    • cites [7] source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In early-phase trials, adagrasib and sotorasib showed promising results in NSCLC and more modest efficacy in colorectal cancer.

    “In early-phase clinical trials, two potent, selective, and irreversible small-molecule KRASG12C inhibitors have shown promising results in non–small-cell lung cancer (NSCLC) and more modest efficacy in colorectal cancer: adagrasib (MRTX849) and sotorasib (AMG510).6,7,10”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] source
    • cites [7] source

      The Results section on responses in cancer patients reports partial responses to MRTX849 (adagrasib) in one lung adenocarcinoma patient and one colorectal cancer patient enrolled in a phase 1b trial. It does not establish that efficacy was more modest in colorectal cancer, and the passages found do not report clinical results for sotorasib (AMG510). Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [10] source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Sotorasib produced an objective response rate of 37.1% and median progression-free survival of 6.8 months in NSCLC and a response rate of 7.1% in colorectal cancer.

    “Sotorasib was associated with an objective response rate of 37.1% and a median progression-free survival of 6.8 months among patients with NSCLC14 and a response rate of 7.1% among those with colorectal cancer.10”
    Quote in the paperNot a substantial claim2 of 2 sources checked

  • May combine two claims.

    Premisecitation

    Adagrasib in a phase 1-2 study produced an objective response rate of 45% in NSCLC and 17% in colorectal cancer.

    “An ongoing phase 1–2 study of adagrasib that involves patients with KRASG12C-mutant cancer has shown an objective response rate of 45% among patients with NSCLC11,12 and 17% among those with colorectal cancer.13”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [11] source
    • cites [12] source
    • cites [13] source

  • May combine two claims.

    Interpretationown data

    In two NSCLC patients without an identified genomic resistance mechanism, histologic transformation from adenocarcinoma to squamous-cell carcinoma was observed, suggesting nongenetic mechanisms of resistance to KRASG12C inhibition may occur.

    “In two patients with NSCLC for whom we were not able to identify a genomic resistance mechanism, we observed histologic transformation from adenocarcinoma to squamous-cell carcinoma, which suggests that nongenetic mechanisms of resistance to KRASG12C inhibition may occur, similar to those observed with other targeted therapies in lung cancer.24-26”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [24] source
    • cites [25] source
    • cites [26] source

  • May combine two claims.

    Findingown data

    Ba/F3 cells expressing KRASG12C are highly sensitive to adagrasib or sotorasib and show dose-dependent inhibition of downstream KRAS effector signaling.

    “Ba/F3 cells that express KRASG12C are highly sensitive to treatment with either adagrasib or sotorasib and show dose-dependent inhibition of downstream KRAS effector signaling”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Expression of G12C/R68S and G12C/Y96C double mutants mediated resistance to sotorasib, whereas G12C/H95D, G12C/H95Q, and G12C/H95R remained sensitive to sotorasib.

    “expression of the G12C/R68S and G12C/Y96C double mutants mediated resistance to sotorasib; in contrast, the G12C/H95D, G12C/H95Q, and G12C/H95R mutants remained sensitive to sotorasib”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Thirty-eight patients treated with adagrasib who had stable disease for at least 12 weeks or an objective response followed by progression were included: 27 with NSCLC, 10 with colorectal cancer, and 1 with appendiceal cancer.

    “A total of 38 patients treated with adagrasib who initially had stable disease for at least 12 weeks or an objective response to therapy followed by subsequent disease progression were included in this study: 27 patients had NSCLC, 10 had colorectal cancer, and 1 had appendiceal cancer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele.

    “Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At resistance, tissue was available for 10 patients, ctDNA for 32 patients, and both for 4 patients.

    “At the time of acquired resistance to adagrasib, tissue was available for analysis for 10 patients, and ctDNA was available for 32 patients; both tissue and ctDNA were obtained from 4 of these patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Pathogenic mutations in other RTK-RAS-MAPK pathway members were detected: NRAS Q61K, BRAF V600E, MAP2K1 K57T/K57N/I99_K104 deletion/E102_I103 deletion, and EGFR A289V.

    “Pathogenic mutations in other receptor tyrosine kinase (RTK)–RAS–MAPK pathway members were also detected in patients with acquired resistance to adagrasib, including NRAS (Q61K in one patient), BRAF (V600E in two patients), MAP2K1/MEK1 (K57T in one patient, K57N in two patients, an I99_K104 deletion in one patient, and an E102_I103 deletion in two patients), and EGFR (A289V in one patient)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Y96C showed high-level resistance to both inhibitors, whereas H95D, H95Q, and H95R caused resistance to adagrasib but not sotorasib.

    “the Y96C drug-binding resistance mutation showed high-level resistance to both inhibitors, whereas the H95D, H95Q, and H95R mutations caused resistance to adagrasib but not to sotorasib.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Acquired bypass mechanisms included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN.

    “Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Biochemical analysis showed R68S, H95D/Q/R, and Y96C blocked drug binding and completely prevented drug-mediated suppression of RAS-MAPK signaling.

    “Biochemical analysis of the response to adagrasib in Ba/F3 cells showed that the R68S, H95D/Q/R, and Y96C second-site mutations in KRASG12C blocked drug binding, as indicated by the absence of KRAS band shift mediated by covalent drug binding, and completely prevented the drug-mediated suppression of RAS–MAPK signaling, as measured by sustained phosphorylated extracellular signal-regulated kinase”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Novel acquired secondary KRAS mutations within the adagrasib-binding pocket were found in 4 patients: Y96C in 1 NSCLC, H95Q and H95R in 1 colorectal, R68S and H95D in 1 NSCLC, and H95R in another colorectal.

    “Novel acquired secondary KRAS mutations within the adagrasib-binding pocket were found in 4 patients, including a Y96C mutation in 1 patient with NSCLC (Fig. 1A and Fig. S1), H95Q and H95R mutations in 1 patient with colorectal cancer (Fig. 1B), R68S and H95D mutations in 1 patient with NSCLC (Fig. 1C), and an H95R mutation in another patient with colorectal cancer (Fig. 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Comparison of resistance patterns between MRTX1257 and sotorasib showed generally strong concordance, although several drug-specific resistance mutations were identified.

    “A comparison of resistance patterns between MRTX1257 and sotorasib showed generally strong concordance, although several drug-specific resistance mutations were identified.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Multiple resistance mechanisms appeared more common in colorectal cancer; among patients with ctDNA sequencing, 4 of 5 colorectal and 2 of 7 NSCLC had multiple resistance alterations, but the difference was not significant.

    “multiple resistance mechanisms appeared to be more common in colorectal cancer; among patients with available ctDNA sequencing, 4 of 5 patients with colorectal cancer and 2 of 7 patients with NSCLC had multiple resistance alterations, although this difference was not significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Five patients acquired codon 12 KRAS mutations that prevent adagrasib binding, and other secondary mutations in the switch II pocket were observed in 4 patients (11% of the cohort) at R68, H95, and Y96.

    “Five patients acquired codon 12 KRAS mutations that prevent adagrasib binding, and other secondary mutations in the switch II drug-binding pocket were observed in 4 patients (11% of the entire cohort) at the R68, H95, and Y96 positions.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    DNA sequencing of tumor-biopsy or ctDNA from 38 patients with acquired resistance to adagrasib described putative mechanisms for 17 (45%) classifiable into three categories: secondary KRAS mutations/amplifications, alternative oncogenic RTK-RAS alterations not directly KRAS, and histologic transformation.

    “We performed DNA sequencing of tumor-biopsy samples or ctDNA from 38 patients with acquired resistance to adagrasib and described putative mechanisms of resistance for 17 patients (45%) that can be classified into three main categories.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The putative resistance mechanisms identified in post-progression samples are causally responsible for clinical resistance to adagrasib.

  • May combine two claims.

    Findingown data

    Additional second-site resistance mutations at oncogenic hotspots cause decreased GTP hydrolysis (e.g., G13D and Q61R) or enhanced GDP-to-GTP nucleotide exchange (e.g., G13D, A59S, and A146P).

    “we identified additional second-site resistance mutations at oncogenic hotspots that cause decreased GTP hydrolysis (e.g., G13D and Q61R) or enhanced GDP-to-GTP nucleotide exchange (e.g., G13D, A59S, and A146P).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    H95 adagrasib-specific resistance mutations occurred in 3 of 38 patients, and each coevolved with multiple other alterations that would confer strong resistance to both adagrasib and sotorasib.

    “the H95 adagrasib-specific resistance mutations occurred in a small number of patients (3 of 38), and each coevolved with multiple other alterations that would confer strong resistance to both adagrasib and sotorasib.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the cohort, multiple genomic alterations within the same patient and acquired gene fusions appeared more prevalent in colorectal cancer than in NSCLC.

    “In our cohort, multiple genomic alterations within the same patient, as well as acquired gene fusions, appeared to be more prevalent in colorectal cancer than in NSCLC.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Adagrasib and sotorasib have shown promising activity in clinical trials in cancers with KRAS G12C mutations.

    “Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Mapping onto the sotorasib-bound KRASG12C structure (6OIM) suggested strong interactions of R68 and Y96 with sotorasib but probably weaker interactions with H95, though additional studies are needed to quantify.

    “mapping of these same residues onto the x-ray crystallographic structure of sotorasib bound to the KRASG12C protein (6OIM)6 suggested strong interactions of R68 and Y96 with sotorasib but probably weaker interactions with the H95 residue, although additional studies would be needed to quantify the strength of these interactions”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites 6OIM

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [6] source

  • May combine two claims.

    Interpretationown data

    Seven of 17 patients (41%) had more than one concurrent potential resistance mechanism, suggesting irreversible covalent KRASG12C inhibition leads to strong selective pressures and convergent evolution of multiple distinct resistance mechanisms.

    “7 of 17 patients (41%) had more than one concurrent potential resistance mechanism identified, which suggests that irreversible covalent inhibition of KRASG12C leads to strong selective pressures and convergent evolution of multiple distinct mechanisms of resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These data suggest that tumor and ctDNA sequencing did not miss a major known molecular driver of adagrasib resistance, though more extensive sequencing could identify other acquired alterations.

    “These data suggest that the tumor and ctDNA sequencing performed on these specimens did not miss a major known molecular driver of adagrasib resistance, but it remains possible that more extensive genomic sequencing of these samples could identify other acquired alterations that may have contributed to resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Y96C appeared to be a clonal resistance event, whereas R68S and H95D/Q/R were identified in ctDNA at low variant allele frequency and with other concurrent mutations, suggesting subclonality or heterogeneity.

    “Although the Y96C mutation appeared to be a clonal resistance event, the R68S and H95D/Q/R secondary KRAS mutations were identified in ctDNA at relatively low variant allele frequency as compared with that of the KRASG12C allele and occurred in the presence of other concurrent resistance mutations, which suggests subclonality or heterogeneity of these mutations across each patient’s burden of dise”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The heterogeneous nature of the tumor and ctDNA sequencing platforms used to characterize acquired resistance is a limitation of the study.

    “The heterogeneous nature of the tumor and ctDNA sequencing platforms that were used to characterize acquired resistance is a limitation of this study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    This study focused on acquired resistance mechanisms in patients treated with adagrasib and did not evaluate patients treated with sotorasib.

    “This study focused on acquired resistance mechanisms in patients treated with adagrasib and did not evaluate patients treated with sotorasib.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Deep mutational scanning defined the landscape of KRAS mutations causing resistance to KRASG12C inhibitors and identified distinct mechanistic classes and drug-specific resistance patterns.

    “In summary, deep mutational scanning has defined the landscape of KRAS mutations that cause resistance to KRASG12C inhibitors. These studies identified distinct mechanistic classes of resistance mutations as well as drug-specific resistance patterns.”
    Quote in the paperSubstantial claim
30 of 30

  • The paper relies on this without support.

    The putative resistance mechanisms identified in post-progression samples are causally responsible for clinical resistance to adagrasib.

    “Putative mechanisms of resistance to adagrasib were identified in 17 of 38 patients (45%).”
    “Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors”

  • The paper relies on this without support.

    The resistance mechanisms observed in the 38 KRYSTAL-1 patients are representative of acquired resistance to adagrasib in KRASG12C-mutant cancers generally.

    “Among patients with KRASG12C-mutant cancers treated with adagrasib monotherapy in the KRYSTAL-1 trial, we performed histologic and genomic analyses of samples obtained at the time of disease progression to identify mechanisms of resistance to adagrasib.”
    “KRASG12C-mutant cancers appear to evolve diverse mechanisms of resistance to adagrasib.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Emerging data suggest that acquired resistance to KRAS G12C inhibitors in colorectal cancer largely involves MAPK signaling reactivation.

    “Emerging data suggest that potential mechanisms of acquired resistance to KRAS G12C inhibitors in colorectal cancer largely include reactivation of MAPK signaling, and future analyses from this trial and others will help to clarify these mechanisms.37”

    From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated <i>KRAS</i> G12C (2023) · cites this paper as [37]

    The Results and Discussion (page not provided) identify acquired alterations in the RTK–RAS–MAPK pathway after adagrasib treatment, including alterations in patients with colorectal cancer. However, the paper does not establish that MAPK signaling reactivation accounts for most acquired resistance in colorectal cancer specifically; its resistance data also concern adagrasib rather than KRAS G12C inhibitors generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Lineage plasticity has an established role in resistance to KRAS-targeted therapies.

    “Despite the established role of lineage plasticity in resistance to KRAS-targeted therapies,26–31 effective therapeutic interventions targeting drivers of lineage plasticity remain lacking.”

    From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [27]

    The Results (page unavailable) report transformation from lung adenocarcinoma to squamous-cell carcinoma in two patients with acquired resistance to adagrasib. The Discussion (page unavailable) says this suggests a possible nongenetic resistance mechanism, but that further investigation is needed to establish how the transformation causes resistance. The paper therefore supports a possible role for lineage plasticity in resistance to a KRASG12C inhibitor, not an established role across KRAS-targeted therapies. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PIK3CA mutations can confer acquired resistance to KRAS G12C inhibitor and KRAS G12C inhibitor-cetuximab combination therapy in patients with NSCLC and CRC.

    “Previous reports have shown that PIK3CA mutations can confer acquired resistance to KRAS G12C inhibitor and KRAS G12C inhibitor–cetuximab combination therapy in patients with NSCLC and CRC34–36.”

    From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [36]

    The Methods (Patients; page unavailable) and Results (Mechanisms of Acquired Resistance to Adagrasib; page unavailable) describe acquired resistance to adagrasib monotherapy in patients with NSCLC and colorectal cancer. They do not identify PIK3CA mutations as a resistance mechanism, and the study did not examine KRAS G12C inhibitor–cetuximab combination therapy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Intrinsic and acquired resistance to sotorasib and adagrasib has been reported in preclinical studies and clinical trials.

    “The discovery of KRAS G12C inhibitors raises great excitement; nevertheless, intrinsic and acquired resistance to sotorasib and adagrasib has been reported in preclinical studies and clinical trials (8–10).”

    From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [8]

    The Methods (Patients) and Discussion document acquired resistance in patients treated with adagrasib, and the Results (Role of Drug-Binding Site Mutations) show resistance to both drugs in cell experiments. The Discussion says the study did not evaluate patients treated with sotorasib and that its clinical acquired-resistance mechanisms were unknown. These passages do not establish intrinsic resistance to either drug. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Resistance to KRAS G12C inhibitors can arise from additional mutations in KRAS or other RAS pathway genes, non-mutational activation of bypass signaling pathways such as MAPK or PI3K, and remodeling of the tumor microenvironment.

    “It is believed that this resistance can arise from a variety of mechanisms, including the emergence of additional mutations in KRAS or other genes involved in the RAS pathway, non-mutational activation of bypass signaling pathways such as the MAPK or PI3K pathways, and diverse remodeling of the tumor microenvironment (8–10).”

    From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [8]

    The Results section (page not provided) identifies acquired KRAS mutations and alterations in other RTK–RAS–MAPK pathway genes as putative resistance mechanisms. The Discussion describes histologic transformation as a possible nongenetic mechanism, but does not establish non-mutational activation of MAPK or PI3K bypass signaling or remodeling of the tumor microenvironment. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Awad, M. M., Liu, S., Rybkin, I. I., Arbour, K. C., Dilly, J., Zhu, V. W., Johnson, M. L., Heist, R. S., Patil, T., Riely, G. J., Jacobson, J. O., Yang, X., Persky, N. S., Root, D. E., Lowder, K. E., Feng, H., Zhang, S. S., Haigis, K. M., Hung, Y. P., Sholl, L. M., Wolpin, B. M., Wiese, J., Christiansen, J., Lee, J., Schrock, A. B., Lim, L. P., Garg, K., Li, M., Engstrom, L. D., Waters, L., Lawson, J. D., Olson, P., Lito, P., Ou, S.-H. I., Christensen, J. G., Jänne, P. A., & Aguirre, A. J.
Affiliations
  • Broad Institute (US)
  • From Dana–Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F., K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H., Y.P.H.), and Brigham and Women’s Hospital (L.M.S., A.J.A.), Boston, and Broad Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and Foundation Medicine (J.L., A.B.S.), Cambridge — all in Massachusetts; Henry Ford Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.), Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego (L.D.E., L.W., J.D.L., P.O., J.G.C.) — all in California; Sarah Cannon Research Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G., M.L.).
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2021-06-24
Volume
384
Issue
25
Pages
2382-2393
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2105281
PMC
PMC8864540
OpenAlex
W3174662367
Semantic Scholar
01a72070b1162777632d392aa5d2ffd80998f017
Cited by
1,247
References
26
Citations by year
2026: 249 · 2025: 290 · 2024: 285 · 2023: 211 · 2022: 164 · 2021: 48
FWCI
116.39
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (1R01CA230267-01A1, 1R01CA230745-01, K08 CA218420-02, P50 CA127003, U01 CA210171)
  • American Cancer Society (CRP-17-111-01-CDD)
  • Mark Foundation for Cancer Research (19-029 MIA)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
KRAS G12C, acquired drug resistance, KRAS inhibitors, cancer therapy resistance, KRAS mutation, resistance mechanisms
MeSH terms
Acetonitriles, Appendiceal Neoplasms, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Piperazines, Protein Conformation, Pyridines, Pyrimidines, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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